Phase II Clinical, Biological and Pharmacological Study of Rapamycin (Rapamune®, Sirolimus) in Patients With Advanced Pancreatic Cancer
- To determine the proportion of patients with previously treated advanced pancreatic
cancer surviving at 6 months after treatment with single agent rapamycin.
- To evaluate the relationship between activation of the PI3/Akt/mTOR/S6K signaling
pathway in tumor tissues and rapamycin activity in this patient population.
- To characterize toxicity of rapamycin in this patient population.
- To determine the response rate, median time to treatment failure, and median survival
of patients with previously treated advanced pancreatic cancer who are treated with
single agent rapamycin.
- To characterize the pharmacokinetics of rapamycin in this patient population.
- To explore pharmacogenomic variables that affect rapamycin pharmacokinetics and
clinical activity in this patient population.
- To determine the pharmacodynamic effects of rapamycin on S6 kinase activation in PBMC,
normal skin, and normal oral mucosa obtained from patients treated with the drug and
its relationship with rapamycin pharmacokinetics and clinical effects.
- To explore biomarkers in tumor tissues that might be associated with rapamycin clinical
OUTLINE: Patients receive oral sirolimus once daily on days 1-28. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.
Patients undergo blood, normal skin, and tumor tissue collection at baseline and
periodically during study for pharmacological, biological, and genotyping studies. Blood
samples are analyzed by LC/MS/MS assay to assess rapamycin pharmacokinetics (PKs) during
courses 1 and 2 and to determine baseline CYP3A4 activity. Samples are also analyzed by
genotyping studies to assess CYP3A4 polymorphisms. Pharmacodynamic activity of rapamycin is
assessed in peripheral blood mononuclear cells isolated from PK blood samples using a kinase
assay to measure S6K activity. Tumor tissue is collected from pretreatment tumor samples
obtained at the time of diagnosis or surgery or by biopsy from patients for whom pre-study
tumor specimens are not available. Patients undergo skin biopsies at baseline and on day 1
of course 2 to obtain samples of normal skin. Patients also undergo oral mucosa smears at
baseline and weekly during course 1. Tumor tissue, normal skin, and oral mucosa samples are
assessed by IHC staining of S6K and p-S6K and by RT-PCR for cyclin D1 and p27.
Primary Purpose: Treatment
Proportion of patients surviving after 6 months
Manuel Hidalgo, MD, PhD
Sidney Kimmel Comprehensive Cancer Center
United States: Food and Drug Administration
|Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins||Baltimore, Maryland 21231-2410|